NEW YORK (GenomeWeb) – Genetic mutations that have been linked to breast or ovarian cancer confer a wide range of increased disease risk – from less than twofold to up to 40-fold, according to a new study conducted by researchers from Stanford University School of Medicine and the Fox Chase Cancer Center.

More and more genetic variants have been associated with breast or ovarian cancer and have become incorporated into panel gene tests, but how much a variant increases cancer risk isn’t always certain. By drawing on a real-world cohort of some 95,600 women who underwent clinical genetic testing, researchers from Stanford and Fox Chase calculated the extent to which 25 different breast or ovarian cancer-linked genes increased disease risk.

As they reported in JCO Precision Oncology yesterday, the researchers relied on two complementary approaches to find that mutations like those in BRCA1 could increase a woman’s risk of developing breast cancer by nearly sixfold, while ones in STK11 could increase her risk of ovarian cancer by 40-fold.

“The results of this study will help to personalize our risk estimates and recommendations for preventive care,” first author Allison Kurian, associate professor of medicine and of health research and policy at Stanford, said in a statement. “A better understanding of cancer risks can help women and their clinicians make better-informed decisions about options to manage cancer risk.”

Kurian and her colleagues examined a cohort of 95,561 women who underwent clinical genetic testing on Myriad Genetics Laboratory’s 25-gene hereditary cancer panel. The panel included the BRCA1, BRCA2, CHEK2, ATM, and STK11 genes, among others.

Testing uncovered 6,775 pathogenic mutations in 6,626 patients, or 7 percent of the cohort. BRCA1 or BRCA2 mutations accounted for 44 percent of the mutations found, while the remaining 56 percent were in other genes.

Kurian and her colleagues conducted both multivariable logistic regression model and matched case-control analyses on this cohort.

For the multivariable logistic regression model analysis, they constructed two models, one to predict breast cancer risk and the other to predict ovarian cancer risk. Through this analysis, the researchers uncovered eight genes associated with breast cancer — ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, PTEN, and TP53 — and 11 associated with ovarian cancer.

Meanwhile, the researchers’ matched case-control analysis of some 19,000 breast cancer patients, 3,700 ovarian cancer patients, and 51,200 cancer-free controls linked the same eight genes to breast cancer. However, their analysis only associated three of the 11 found through modeling with ovarian cancer risk — BRCA1, BRCA2, and RAD51C.

These genes, though, had varying effects on cancer risk, the researchers reported. BRCA1 mutations, for instance, increased breast cancer risk by nearly sixfold and TP53 mutations by fivefold, while ATM mutations boosted it by less than twofold.

Similarly for ovarian cancer, STK11 mutations were associated with a 40-fold increase in disease risk and BRCA1 with a 12-fold increase, while ATM was associated with less than a twofold increase in risk.

As patient care guidelines are based upon a woman’s lifetime risk of disease, the researchers said that their estimates could inform discussions between healthcare providers and patients.

“As more patients with cancer and at risk of cancer get access to genetic testing, we will gain a more comprehensive view of which genes have an impact on cancer risk and how large those risks are,” senior author Michael Hall, associate professor of medicine at Fox Chase Cancer Center, said in a statement. “Some genetic mutations will necessitate increased screening, but others may be low enough that we don’t need to do more than standard prevention and early detection.”

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